Modeling of mammalian olfactory receptors and docking of odorants

Abstract

Olfactory receptors (ORs) belong to the superfamily of G protein-coupled receptors (GPCRs), the second largest class of genes after those related to immunity, and account for about 3 % of mammalian genomes. ORs are present in all multicellular organisms and represent more than half the GPCRs in mammalian species (e.g., the mouse OR repertoire contains >1,000 functional genes). ORs are mainly expressed in the olfactory epithelium where they detect odorant molecules, but they are also expressed in a number of other cells, such as sperm cells, although their functions in these cells remain mostly unknown. It has recently been reported that ORs are present in tumoral tissues where they are expressed at different levels than in healthy tissues. A specific OR is over-expressed in prostate cancer cells, and activation of this OR has been shown to inhibit the proliferation of these cells. Odorant stimulation of some of these receptors results in inhibition of cell proliferation. Even though their biological role has not yet been elucidated, these receptors might constitute new targets for diagnosis and therapeutics. It is important to understand the activation mechanism of these receptors at the molecular level, in particular to be able to predict which ligands are likely to activate a particular receptor ('deorphanization') or to design antagonists for a given receptor. In this review, we describe the in silico methodologies used to model the three-dimensional (3D) structure of ORs (in the more general framework of GPCR modeling) and to dock ligands into these 3D structures.

Keywords: 3D structure modeling; G protein-coupled receptors; Homology modeling; Ligand docking; Virtual screening.

Fig. 1

Eleven G protein-coupled receptor templates and three olfactory receptor multiple sequence alignments. Starting and ending positions of transmembrane helices (TMHs) are indicated. Green boxes highlight conserved positions previously reported in the literature for olfactory receptors. Position 50 of the Ballesteros–Weinstein numbering scheme is shown in orange. N-terminus residues are missing in the X-ray structure for the dopaminergic, histamine H1, and sphyngosine 1-phosphate receptors